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Biomedical subjects

M George

Publications and source records attributed to M George.

At least 127 records · Page 7Linked to original sources
PubMed1993

The developmental pattern of rabbit brain insulin and insulin-like growth factor receptor expression.

To examine the effect of development on rabbit brain insulin and insulin-like growth factor (IGF) receptor expression, we characterized and quantitated receptor mRNAs by Northern blot analysis and affinity-labeled ligand bound receptors by SDS-PAGE and autoradiography. At various stages of development ranging from 23 to 30 day gestational (term approximately 31 days), 1 to 10 day postnatal ages and the adult, no change in the whole brain insulin receptor mRNA (7.0, 6.0 and 5.5 kb) and affinity-labeled receptor protein (approximately 125 kDa) levels was observed. The IGF-I receptor mRNA (11.5, 6.5 and 4.5 kb) and affinity-labeled receptor (approximately 125 kDa) protein levels declined during the neonatal stages of development. In the case of the IGF-II receptor, while the mRNA levels (9.0 and 4.5 kb) remained constant, the corresponding affinity-labeled receptor protein (approximately 230 kDa) declined with maturation. We conclude that a differential regulation of brain insulin, IGF-I and IGF-II receptor expression occurs during development.

Animals↗
PubMed1993

Phase I trial of a 5-day infusion of L-leucovorin plus daily bolus 5-fluorouracil in patients with advanced gastrointestinal malignancies.

The combination of leucovorin [(6d,l)-5-formyl-tetrahydrofolate] and 5-fluorouracil (5-FU) has increased efficacy compared to 5-FU alone as treatment of advanced colorectal cancer. Leucovorin is metabolized to methylene tetrahydrofolate, which potentiates the antitumor actions of 5-FU by forming a ternary complex of thymidylate synthase, fluorodeoxyuridine and methylene tetrahydrofolate. Only l-leucovorin is metabolized to methylene tetrahydrofolate and forms this ternary complex. However, d-leucovorin may not be inert. d-Leucovorin may impair cellular uptake and metabolism of l-leucovorin, thereby inhibiting the actions of l-leucovorin. Because of this possible limitation to the effectiveness of racemic leucovorin, we have begun to explore the effects of the pure, biologically active isomer, l-leucovorin. In this phase I trial, patients with advanced gastrointestinal malignancies were treated with a 5-day continuous infusion of l-leucovorin and daily intravenous boluses of 5-FU at 370 mg/m2. The dose of l-leucovorin was escalated in groups of three patients at four doses, 200 mg/m2 per day, 400 mg/m2 per day, 700 mg/m2 per day and 1000 mg/m2 per day. Treatment was repeated every 28 days. Seventeen patients with advanced gastrointestinal cancers entered the trial. Sixteen patients were evaluable for toxicity. Toxicity was similar to that expected for leucovorin plus 5-FU. The most common severe toxicities (and the number of patents affected) were: diarrhea (2), mucositis (2), nausea/vomiting (1), and abdominal/rectal pain (2). The maximum tolerated dose of l-leucovorin was 700 mg/m2 per day. Twelve patients were evaluable for response. One complete, one partial and one minor response were observed. All responses occurred among the nine patients with colorectal carcinomas. The combination of l-leucovorin and 5-FU is well tolerated by patients and appears active for treatment of advanced colorectal carcinomas. Additional clinical trials are necessary to determine if l-leucovorin is more effective than d,l-leucovorin for modulating the effectiveness of 5-FU.

Adenocarcinoma↗
PubMed1993

Neuroendocrine and neurochemical responses to novelty stress in young and old male F344 rats: effects of d-fenfluramine treatment.

To understand some of the mechanisms underlying the neuroendocrine and neurochemical changes associated with aging, we administered the serotonin [5-hydroxytryptamine (5-HT)] releaser and reuptake inhibitor d-fenfluramine (d-FEN; 0.0, 0.2, or 0.6 mg/kg/day, p.o) for 30-38 days to young (4 months) and old (22 months) F344 male rats. Rats were stressed by placement into a novel open field (OF) for 20 min before sacrifice. Control animals were sacrificed immediately upon removal from their home cage (HC). Old rats exhibited less (p < 0.05) exploratory behavior than young rats, which was not altered by treatment with d-FEN. Old HC rats also had higher (p < 0.05) basal plasma levels of adrenocorticotropic hormone (ACTH) and prolactin (PRL) than young HC rats. Old OF rats showed higher (p < 0.05) levels of ACTH and corticosterone (CORT) than young OF animals. A stress-induced increase in PRL secretion was not observed in old rats. Subchronic low-dose d-FEN normalized the enhanced ACTH and CORT responses of old animals to novelty. In addition to these endocrine changes, stress-induced increases in medial frontal cortex (MFC) dopamine (DA) and norepinephrine (NE) turnover also were observed. The increase in NE turnover was greater (p < 0.01) in old than in young rats. d-FEN treatment blocked the stress-induced increase in MFC NE but not MFC DA turnover in both young and old rats. These data support a role for 5-HT and/or NE in some age-related neuroendocrine perturbations and suggest that increased 5-HT neurotransmission can normalize the hyperactivation of the hypothalamo-pituitary-adrenal axis of old male rats.

Adrenocorticotropic Hormone↗
PubMed1993

Comparison of the pharmacokinetics of methohexital during cardiac surgery with cardiopulmonary bypass and vascular surgery.

The aim of this study was to assess the pharmacokinetics of methohexital (ME) in major vascular surgery (VASC) and to compare these data with the pharmacokinetics of ME during hypothermic cardiopulmonary bypass (HCPB) (temperature: 28 degrees C) and normothermic cardiopulmonary bypass (NCPB) (temperature: 37 degrees C). An ME bolus (2 mg/kg) was administered to 8 VASC patients at the start of surgery and to 11 HCPB patients and 11 NCPB patients at the start of cardiopulmonary bypass (CPB). Twenty-one arterial blood samples were withdrawn over the following 24 hours for ME assays. All of the patients were given similar anesthesia (fentanyl, diazepam) and muscle relaxation (pancuronium). In the VASC group, ME total body clearance (TBC) was 6 +/- 2 mL/kg/min (mean +/- SD), which is less than in previous studies. When comparing HCPB and NCPB groups, elimination half-life (T1/2), TBC, volume of distribution (VD), area under the curve (AUC), and mean residence time (MRT) were similar. When comparing VASC and CPB patients, TBC and VD were greater in CPB patients than in VASC patients; thus, T1/2 (equal to 0.693 x VD/TBC) was similar. AUC was smaller in CPB patients because of hemodilution, but MRT was similar. It is concluded that ME clearance is lower in patients undergoing major vascular surgery than in healthy patients. The temperature and the duration of CPB do not seem to substantially influence the pharmacokinetics of ME when a bolus is administered. Parameters such as AUC, TBC, and VD appear modified by hemodilution during CPB; however, T1/2 and MRT, which allow comparisons between CPB and non-CPB patients, were similar in these patients.

Blood Proteins↗
PubMed1993

Clinical and pharmacological study of intrahepatic artery infusion of thiotepa.

Twenty patients with primary or metastatic liver cancer were treated on a clinical and pharmacological study with intrahepatic artery infusion of Thiotepa. Toxicity was tolerable and included nausea and fatigue. Uncommon side effects were myelosuppression, abdominal pain and anemia. One patient with gallbladder cancer had a partial response for 11 (+) months. Recommended dose of Thiotepa for future Phase II clinical trials is 1.0 mg/kg. Pharmacokinetics of intrahepatic Thiotepa revealed an extraction ratio similar to that reported for cisplatin. The data suggest increased hepatic clearance for Thiotepa either by binding or metabolism.

Aged↗
PubMed1993

14-Day continuous infusion of mitoxantrone in hormone-refractory metastatic adenocarcinoma of the prostate.

A dose-finding investigation was conducted with mitoxantrone administered as 14-day continuous infusions to patients with hormone-refractory metastatic adenocarcinoma of the prostate. Fifteen men participated in four dosage groups: mitoxantrone 1.0, 1.25, 1.4, and 1.5 mg/m2/day; a treatment cycle was defined as a dose of mitoxantrone given over 2 weeks, followed by 2 weeks of monitoring prior to the next course. The patients received 1 to 10 courses, with the majority receiving 1 to 3. The maximum tolerated dose was 1.25 mg/m2/day for 14 days of continuous infusion. Two patients discontinued treatment because of gastrointestinal effects. Most adverse clinical experiences were mild or moderate in intensity. A decrease in prostate-specific antigen (PSA) response was seen after one course in 6 of 14 patients who had PSA measurements. Stable disease was achieved in 40% of the evaluable patients, and some quality of life parameters improved. Further clinical trials with mitoxantrone are indicated in patients with prostatic cancer, especially in those who have had less previous treatment.

Adenocarcinoma↗
PubMed1993

Substitution of l-leucovorin for d,l-leucovorin in the rescue from high-dose methotrexate treatment in patients with osteosarcoma.

Studies in which high-dose methotrexate (HDMTX) is used for the treatment of osteosarcoma have utilized commercial formulations of d,l-leucovorin (leucovorin calcium) for rescue from potential methotrexate (MTX) toxicity. These formulations are racemic mixtures containing equal amounts of d and l isomers of leucovorin. All of the available data indicate that the l isomer is the pharmacologically active diastereomer. A clinical study was conducted to determine if l-leucovorin was as safe and efficacious as d,l-leucovorin in the rescue of patients with osteosarcoma who were treated with HDMTX (12.5 g/m2 over 6 h). Because d,l-leucovorin consists of equal proportions of d and l isomers, l-leucovorin was administered at half the usual dose of d,l-leucovorin. In patients with delayed methotrexate excretion, l-leucovorin doses were escalated from 7.5 to 50 mg every 3 h until the MTX level was 0.3 mumol/l or less. Due to the low incidence of osteosarcoma, a control group of patients previously treated with d,l-leucovorin was utilized for comparison. Efficacy of l-leucovorin was determined by its ability to prevent HDMTX-associated toxicity. Demographic and clinical toxicity data from three patients who received 22 courses of MTX rescued with l-leucovorin were compared with data from six patients who had received 42 MTX courses rescued with d,l-leucovorin. Some liver function abnormalities and leukocyte elevations were found in both groups and were attributed to MTX administration. No clinical toxicity attributable to l-leucovorin was observed. l-Leucovorin in half the d,l-leucovorin dose was (equally) effective as a rescue treatment.

Adolescent↗
PubMed1993

Detection and comparison of DNA adducts after in vitro and in vivo diesel emission exposures.

Development of methods to evaluate certain classes of polycyclic aromatic compounds (PAC) detected in complex mixtures to which humans are exposed would greatly improve the diagnostic potential of 32P-postlabeling analysis. Identification of DNA adduct patterns or specific exposure-related marker adducts would strengthen associations between observed DNA adducts and exposures to different environmental pollutants (e.g., kerosene, cigarette smoke, coke oven, and diesel). We have compared diesel-modified DNA adduct patterns in various in vitro and in vivo rodent model systems and compared them to DNA reactive oxidative and reductive metabolites of 1-nitropyrene. The formation of nitrated polycyclic aromatic hydrocarbon (nitrated PAH) DNA adducts, derived from the metabolism of diesel extract constituents, was enhanced relative to other PAH-derived DNA adducts via xanthine oxidase-catalyzed nitroreduction. These adducts were detectable only by the butanol extraction version of the postlabeling analysis. Five major DNA adducts were detected in human lymphocytes treated in vitro with diesel extract. A major adduct detected in human lymphocytes treated in vitro with diesel extract comigrated with a major adduct detected in lymphocyte DNA treated with benzo[a]pyrene (BaP) alone. Other adducts that co-migrated with the major BaP-derived adducts were detected in skin and lung DNA isolated from rodents topically treated with (50 mg) diesel extract and the major adduct detected in calf thymus DNA treated with rat liver S9 and diesel particle extract. Postlabeling of lung DNA isolated from rodents exposed via lung inhalation for 24 months to diesel combustion emissions resulted in the formation of a major nuclease-P1-sensitive DNA adduct that did not co-migrate with the major BaP-diol epoxide adduct.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Comparison of DNA adducts from exposure to complex mixtures in various human tissues and experimental systems.

DNA adducts derived from complex mixtures of polycyclic aromatic compounds emitted from tobacco smoke are compared to industrial pollution sources (e.g., coke ovens and aluminum smelters), smoky coal burning, and urban air pollution. Exposures to coke oven emissions and smoky coal, both potent rodent skin tumor initiators and lung carcinogens in humans, result in high levels of DNA adducts compared to tobacco smoke in the in vitro calf thymus DNA model system, in cultured lymphocytes, and in the mouse skin assay. Using tobacco smoke as a model in human studies, we have compared relative DNA adduct levels detected in blood lymphocytes, placental tissue, bronchoalveolar lung lavage cells, sperm, and autopsy tissues of smokers and nonsmokers. Adduct levels in DNA isolated from smokers were highest in human heart and lung tissue with smaller but detectable differences in placental tissue and lung lavage cells. Comparison of the DNA adduct levels resulting from human exposure to different complex mixtures shows that emissions from coke ovens, aluminum smelters, and smoky coal result in higher DNA adduct levels than tobacco smoke exposure. These studies suggest that humans exposed to complex combustion mixtures will have higher DNA adduct levels in target cells (e.g., lung) as compared to nontarget cells (e.g., lymphocytes) and that the adduct levels will be dependent on the genotoxic and DNA adduct-forming potency of the mixture.

Adult↗
PubMed1993

[A comparison of 3.5% dextran 40 and 4% albumin used as volume expansion solutions following heart surgery. Effects on the hemodynamic parameters and the oncotic colloidal pressure].

Dextran 40 (3.5%), a synthetic colloid solution used as a volaemic expander was compared to albumin 4% in 30 patients (15 in each group) during the first twenty hours after cardiac surgery. The patients were administered 500-600 ml.m-2 either dextran 40 or albumin at a rate of 10-12 ml.kg-1 x h-1 between 2nd and 4th postoperative hour. In the two groups, heart rate and mean arterial pressure did not change significantly but left and right filling pressures and cardiac index increased similarly. Colloid oncotic pressure and haemoglobin varied in the same way in the two groups. Proteinemia and albuminaemia were increased significantly in the albumin group during all the study. Diuresis was not different in the two groups. No side effect was observed. Dextran 40 was efficient and could be used as a volaemic expander after cardiac surgery.

Adolescent↗
PubMed1992

Developmental regulation of insulin in the mammalian central nervous system.

We delineated the ontogeny of rabbit brain insulin concentrations to define the regulatory role of development on this hormone in the central nervous system. Employing a sensitive ELISA, we observed higher concentrations in the late gestation fetal brain (approximately 80-90 ng/g) and early neonatal brain (approximately 195 ng/g) in comparison to the adult (approximately 32 ng/g; P less than 0.01). Further, we characterized this hormone to determine the identity of insulin (or an insulin-like substance) in brain. Employing porcine/bovine or rabbit insulin as standards, we observed that brain insulin mimicked authentic insulin in its migration on SDS-polyacrylamide and native gel electrophoresis, immunogenicity on Western blot analysis, and its elution profile on immunoaffinity column chromatographic, and high performance liquid chromatographic separation. We then examined the developmental effects on circulating and cerebrospinal fluid (CSF) radioimmunoassayable insulin levels. No statistically significant differences (ANOVA) existed through development in either the serum or CSF insulin levels. Employing multiple regression analysis, no correlation was evident between brain and either serum or CSF insulin concentration. A search for insulin mRNA by Northern blot analysis yielded minute amounts of atypical large sized transcripts. We conclude that the insulin peptide in the central nervous system closely resembles (or is identical to) circulating insulin in many properties and that there is a developmental increase in brain insulin concentrations, the maximal peak occuring in the late gestation fetus and early neonate. Insulin concentrations in brain demonstrate no conventional relationship to either the serum or CSF insulin levels, suggesting an additional source of peptide, which contributes beyond that which is available via the circulation. The amounts of insulin present within the central nervous system are minute (difficult to detect) but in the range (10-100 ng) where the hormone can interact with either insulin or insulin-like growth factor I (IGF-I) receptors that are abundantly present on developing brain cells, thereby executing the biological function of the hormone.

Aging↗
PubMed1992

The LCR-like alpha-globin positive regulatory element functions as an enhancer in transiently transfected cells during erythroid differentiation.

A positive regulatory element (PRE) similar to the locus control region (LCR) of the human beta-globin gene cluster has recently been identified 40 kb upstream of the human zeta-globin mRNA cap site (Higgs D.R. W.G. Wood, A.P. Jarman, J. Sharpe, J. Lida, I.M. Pretorius, and H. Ayyub. 1990). We investigated the influence of the alpha PRE on human alpha-globin promoter activity in transiently transfected cells. The introduction of the alpha PRE into alpha-globin promoter/CAT expression constructs increased alpha-globin promoter activity by 15-30 fold in a human erythroid cell line (Putko) as well as in mouse erythroleukemia cells (MELCs) induced with hexamethylene bisacetamide (HMBA). When these constructs were introduced into uninduced MELCs or HeLa cells, only a 2-3 fold increase in alpha-globin promoter activity was observed. Deletion of 600 bp of alpha-globin 5' flanking sequences containing six putative SP1-binding sites had no significant effect on levels of alpha-globin promoter enhancement by the alpha PRE. We further demonstrated that the alpha PRE and HS2 of the beta-LCR could similarly enhance transcriptional activity of the SV40 early promoter in HMBA induced MELCs. Finally, we showed that alpha-globin promoter activity in the presence of the alpha PRE increased with continued HMBA exposure and was coincident with transcriptional activation of endogenous globin genes.

Acetamides↗
PubMed1992

Preliminary evidence for methamphetamine-induced behavioral and ocular effects in rat offspring following exposure during early organogenesis.

Gravid Sprague-Dawley CD (VAF) rats received 50 mg/kg (d,l)-methamphetamine (MA) HCl (expressed as free base, N = 15) or distilled water (N = 6) by SC injection x 2/day in a 3 ml/kg volume on embryonic (E) days 7-12. Control rats were pair-fed to MA-exposed dams on days E7-18. No control dams failed to deliver; however, of 15 MA-exposed dams 4 did not deliver (2 died and 2 had completely resorbed litters). One additional MA litter had all the offspring die shortly after birth. There was no difference between groups on offspring postnatal (P) body weight. The offspring exposed prenatally to MA had significantly lower olfactory orientation scores (P9, 11, 13) to their home cage scent. In a test of early activity (P10, 12, 14) the MA-exposed progeny were marginally less active than controls. MA-exposed offspring exhibited hyperreactivity and marginally shortened response latency on a test of acoustic startle (P27). Motor activity showed no differential response in MA treated or control offspring to MA (P63) or fluoxetine challenge (P70). However, the MA offspring were more active than controls with respect to central and side activity during the second week of testing. No group differences were found for performance in a straight swimming channel or on the number of errors committed or latency to escape in a complex (Cincinnati) water maze (P84). Prenatal exposure to MA also induced eye defects (i.e., anophthalmia, microphthalmia and folded retina) in 16.7% of the progeny. However, MA did not effect hippocampal or neostriatal monoamine levels when measured on P28.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1992

[Vascular effects of urapidil administrated during extracorporeal circulation].

Urapidil exerts a combined central sympathetic and peripheral alpha-1 adrenergic receptor inhibition. Urapidil induces arterial vasodilation but its effects on venous capacitance are more difficult to assess. During cardiopulmonary bypass with constant perfusion index (2.4 l.min-1 x m-2) total peripheral resistance varies similarly as to arterial pressure and, as the apparatus venous reservoir is filled continuously by simple gravity from the right atrium, a decrease in venous blood reservoir level reflects an increased venous capacitance. Twenty-six patients undergoing cardiac surgery were anaesthetized with fentanyl and midazolam and randomly assigned to one of two groups. During normothermic cardiopulmonary bypass, group 1 was administered i.v. urapidil 12.5 mg and group 2 a placebo. In group 1, arterial pressure decreased by 33 +/- 14% (mean +/- SD) at the second minute while total peripheral resistance decreased from 1,384 +/- 255 to 927 +/- 193 dyn.s.cm-5. Then this two parameters regained group 2 values after the eighth minute. Reservoir blood level was lower in group 1 than in group 2 from the second to the eight minute (p < 0.05) with maximum effect at 7 minutes. It is concluded that urapidil exerts arterial and venous dilation. Its arterial effects seem greater during normothermic cardiopulmonary bypass than in normal conditions and its maximum venous effects seem to occur after its maximum arterial effects. The short duration of action may be due to the small dose administered.

Aged↗
PubMed1992

Diabetes mellitus in The Gambia, west Africa.

A register of diabetic patients attending the Royal Victoria Hospital, Banjul, The Gambia, was kept and data on hospital admissions recorded over a 1-year period. Two hundred and sixty-nine patients (110 men, 159 women) were registered of whom 66 (25%) were receiving insulin. Seventy-five patients (28%: 40 men, 35 women) were newly diagnosed. There were significant differences in age (p less than 0.001) and obesity (p less than 0.001) between men and women and between patients with different types of diabetes. There were 95 hospital admissions (5.2%) related to diabetes, as were a fifth of medical out-patient attendances. Ketoacidosis was the major cause of death while foot infections were more common (p less than 0.01) in women. Diabetes imposed a heavy burden on the health services of The Gambia, a small developing country in West Africa; more than 3.6% of the annual health budget was spent on the treatment of diabetic patients.

Adult↗